Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects (e.g., most commonly pulmonic stenosis and hypertrophic cardiomyopathy) and skeletal anomalies (Noonan, Am. J. Dis. Child. 116:373-80, 1968; Allanson, J. Med. Genet. 24:9-13, 1987). Other frequently associated disorders include a webbed neck, chest deformities, cryptorchidism, mental retardation, and bleeding diatheses. NS is a relatively common syndrome with an estimated incidence of 1:1000 to 1:2500 live births.
Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50% of NS (Carta et al., Am J Hum Genet 79:129-35, 2006; Fragale et al., Hum. Mutat. 23, 267-77, 2004; Schubbert et al., Nat Genet 38:331-6, 2006; Tartaglia et al., Am. J. Hum. Genet. 70:1555-63, 2002; Tartaglia et al. Nat. Genet. 29:465-8, 2001). PTPN11, the first NS-associated gene identified (Tartaglia et al., 2001; see also U.S. Pat. Pub. No. 2003/0125289), encodes the non-membranous protein tyrosine phosphatase, SHP-2, that primarily serves positive regulatory roles in signal transduction, particularly via the receptor tyrosine kinase (RTK)-mediated RAS-MAPK pathway. Most mutations perturb the switch between the basally inactive and phosphotyrosine-bound active conformations of SHP-2, shifting the equilibrium towards the latter Fragale et al., 2004; Tartaglia et al., 2001; Keilhack et al., J. Biol. Chem. 280:30984-93, 2005; Tartaglia et al., Am. J. Hum. Genet. 78:279-90, 2006).
The clinical diagnosis of NS depends on recognition of the symptoms by a knowledgeable doctor. Nevertheless, substantial phenotypic variations, including mild or subtle cases, make the diagnosis difficult. Furthermore, the facial characteristics become less apparent with progressing age, so NS will sometimes remain undiagnosed. A genetic test for diagnosing Noonan syndrome involves detecting mutations in PTPN11 and KRAS, but PTPN11 and KRAS mutations account for only 50% of patients suspected of having NS. Therefore, there remains a need to identify other specific gene(s) involved in Noonan syndrome—such identification would aid in the diagnosis (in particular, early diagnosis) and treatment of a broader population of patients afflicted with NS.